Heterocyclic Chemistry

Neooxazolomycin (Part1)

2007-07-31T06:42:00.000-07:00

Onyango, Tsurumoto, Imai, Takahashi, Ishihara, Hatakeyama. ACIEE, 2007, Early View, DOI: 10.1002/anie.200702229

Neooxazolomycin was isolated by Uemura in 1985, together with the oxazolomycin, this oxazole polyene lactam-lactone antibiotics was synthesized first by Kende in 1990.

But I find interesting the way to achieve the synthesis of the furo-pyrrole moiety (lactam-lactone) by Hatakeyama. This synthesis, I present you, starts from the reaction of heptynol (see below) and tetramethyldisilazane ((HMe2Si)2NH) provides hydromethylsilylether (not shown) which upon treatment with Pt(dvds) as catalyst in THF gives the cyclic siloxane. After iodination with I2 in presence of CsF in a DMF/MeOH mixture, the iodoalkenol is obtained in 82% (3 steps). The synthesis continues with the oxidation of the alcohol under Jones conditions, and the carboxylic acid is condensed with 2-(methylamino)malonate through the acid chloride to provide the amide in 62% Yield (3 steps). The cyclization of the alkenyl amide with the Pd(OAc)2/PPh3 couple, K2CO3 and nBu4NBr in solution in DMF results in the formation of the alkylidene-pyrrolidinone in 84% yield. The crucial step is undoubtedly the stereoselective dihydroxylation using OsO4/NMO with a concomitant lactonization to furnish lactam-lactone moiety in 88% yield.

A very interersting paper with a lot of different chemistry: Reformatsky, Stille, Nozaki-Hiyama-Kishi, Tamao hydrosilylation, Dihydroxylation.

8-hydroxyquinoline vs 4,7-dimethoxy-1,10-phenantroline

2007-07-18T00:57:00.000-07:00

I always read paper from Buchwald, not because it is interesting, but it can be useful, and in particular the last JOC dealing with N-arylation of imidazoles and benzimidazoles. I jumped directly to the support. info. to see the synthesis of the phenantroline ligand.

The author indicates that the ligand has been synthesized according to a combination of procedures, but the most relevant is the following one: Tetrahedron 2002, 58, 9095.

The first step consists in the synthesis of the methoxyalkylidene derivative of meldrum's acid with trimethylorthoformate, and a subsequent double Michael addition of phenylene diamine to perform the disubstituted aminobenzene in 77% yield. After, a thermal decarboxylation/cyclization in diphenylether at 250°C, the 4,7-dihydroxyphenantroline is isolated in 86%. The end of the reaction is quite classical, a chlorination in refluxing POCl3 followed by a nucleophilic substitution with NaOMe in 74% over 2 steps.

Nice way to synthesize phenantrolines...

Nevertheless, if you read quickly this publication (abstract and conclusion), it seems this phenantroline is the best ligand for the N-arylation of imidazoles and benzimidazoles. According to me, it is not. Of course this ligand is excellent. But my first choice will be 8-hydroxyquinoline. Because, first, the regioselectivity concerning the 4-methylimidazole is better (63:1), otherwise in almost all the cases the yields are quite the same, and finally (the best reason) it is cheaper....

Copper-Catalyzed N-Arylation of Imidazoles and Benzimidazoles

Ryan A. Altman, Erica D. Koval, and Stephen L. Buchwald

J. Org. Chem.; 2007

Lot of Work and Colorectal cancer.....

2007-07-13T12:52:00.000-07:00

Oh My god!!!! I am just opening my RSS reader, it indicates 170 new articles ( and don't have Elsevier RSS feed), so I think I will work this week-end....after the beach.....
And a very small post for my friend Pierre who indicates me a very potent molecule for the treatment of colorectal cancer....the vatalanib a tyrosine kinase inhibitor and should be on the market in 2008...(Sorry today no chemistry).

3-MCR of Barbiturate

2007-07-12T02:08:00.000-07:00

My boss give me a paper from Italian guys about my future research project dealing with the multi-component synthesis of barbiturates, using unsymetrical carbodiimide (N-aryl, N'-alkyl carbodiimide), malonic acid ester and an alkyl halides.

Indeed, it is a sequential multicomponent reaction, which is performed in a sealed tube. First, carbodiimide (1.1equiv.) and malonic acid ester (1equiv.) are mixed together at RT overnight in acetonitrile (0.1M), and then K2CO3 (2.1equiv.) and alkyl halide (4equiv.) were added and heated at 120°C for 30min. I think I will do this step in the microwave oven....for 5min.....

The yields obtained with this type of reaction are between 52 and 90%, which is good, but there is still drawbacks first of all the R1 must be introduced before the MCR, second, depending on the substituents needed the carbodiimides have also to be synthesized before, and third we have a racemic mixture....

Org. Lett.; (Letter); 2007; 9(5); 841-844. DOI: 10.1021/ol063074+

Neurogenesis in Skeletal Muscle

2007-07-11T12:25:00.000-07:00

This week in JACS, Korean guys have published a very interesting paper concerning the induce neurogenesis of human skeletal muscle cells.

Upon Neurodazine (Nz) treatment of C2C12 cells (skeletal muscle cells) develop a neuronal phenotype, they have shown also using a mouse 20K DNA chips that Nz upregulated in particular gene which is involved in inducing neuronal differentiation.

From a chemical point a view, these guys have synthesized an imidazole library with different substituents in 1,2, 4 and 5 on solid support (Wang resin), with amino-conjuguated diethylene glycol, more than 300 imidazoles have been obtained with a purity >70%. Three different polymer supported platforms have been realized, you will see below only one example using a benzylamine derivative. The imidazole ring has been synthesized with the classical multicomponent reaction with an aldehyde (R1CHO) , an 1,2-dicarbonyl compound (R2COCOR3) , and with ammonium acetate.

R1, R2, and R3 are mainly aromatic compounds
To see the other platforms, chemistry and biological tests see Supporting info.

Synthetic Small Molecules that Induce Neurogenesis in Skeletal Muscle
Darren R. Williams, Myung-Ryul Lee, Young-Ah Song, Sung-Kyun Ko, Gun-Hee Kim, and Injae Shin
JACS, 2007, DOI: http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/ja072817z

Total synthesis of Iromycins

2007-07-10T12:03:00.001-07:00

Today a small post concerning the synthesis of pyridone starting from pyrone, which is not only a valuable tool in Diels-Alder reaction but also for the preparation of "pyridine" ring.

Iromycins are microbial metabolites which exibit an interesting biological activity as NO synthase inhibitors, their structures are fully substituted pyridones.
Recently, von Zezschwitz et al. from Gottingen in Germany, described the synthesis of Iromycin A and different analogues via cross-coupling reaction.

This synthesis of the nucelus starts with the construction of the pyrone ring by successive condensation reactions followed by cyclization. The starting material, the ethyl 2-methyl-3-oxo-butanoate 1 is lithiated by LDA at 0°C, and alkylated with propyl iodide to provide 2 in 56% yield, a second metalation also with LDA give the acetylated intermediates 3 using N-acetylimidazole as acetylating agent. The subsequent lactonization is performed on the crude employing DBU to furnish the desired 2-pyrone 4.

The pyrone in hand, the preparation of pyrone 4 has been realized with aqueous ammoniac in dioxane at 120°C in a sealed tube, through a 1,6-michael addition-ring opening-ring closure procedure in 75%.

Interestingly, the same pyridone can be obtained by a stepwise way, with the same type of reaction in presence of hydrazine, the intermediate hydrazone 5 is hydrolyzed with potassium hydrogenolsulfate to supply the N-aminopyridone 6. The diazotation of 6 in acetic acid lead to the 2-pyrone in 88% (on 2 steps).

Of course, some guys will tell me, this type of reactions are well-known, since "century".
But I like this type chemistry, this is not the usual clockwise metalation of pyridine or synthesis of pyridine by DA reaction.....

Iromycins: A New Family of Pyridone Metabolites from Streptomyces sp. II. Convergent Total Synthesis, Streptomyces sp. II. Convergent Total Synthesis
Heydar Shojaei, Zhen Li-Bo¨hmer, and Paultheo von Zezschwitz, JOC, 2007, 72, 5091.

Synthesis of 2-methyltryptamine

2007-07-04T13:14:00.000-07:00

As some people probably noticed, I like OPRD (Organic Process Research & Development), of course chemically speaking nothing weird, only classic chemistry but scalable synthesis and no COLUMN, for me the dream.
And sometimes we can find very interesting stuff, as this synthesis of the 2-methyltryptamine by the Grandberg methodology, which is indeed a modified Fisher indole synthesis.
This chemistry starts with the formation of the hydrazone between the phenylhydrazine and the 5-chloropentan-2-one, after cyclization and isomerization from iminium to enamine form, the rearrangment takes place to afford the tricyclic intermediates, which after loss of a proton provides the 2-methyltryptamine with 42% in almost 20 Kg scale!!!!! in A 800L reactor!!!!!!!!!!

Optimization and Scale-Up of the Grandberg Synthesis of 2-Methyltryptamine
Joel Slade, David Parker, Michael Girgis, Raeann Wu, Scott Joseph, and Oljan Repi
OPRD, 2007

Synthesis of 1-chloro-3-aminopyrazolylisoquinoline

2007-07-04T07:57:00.000-07:00

In doing research on the latest patents on WIPO (28.06.2007), I found a patent from Hoffmann-La Roche describing the synthesis of different isoquinoline aminopyrazoles, this type of molecules are protein kinase inhibitors (Aurora A)(I don't find it on Kinasepro's blog, but maybe I am wrong, otherwise nobody's perfect...).

I present here, only the synthesis of the main nucleus.

Interestingly, this synthesis starts with 1-indanone, which upon the treatment of butylnitrite, furnishes the 2-oxime derivative in 2 hours and in 65% yield (19.5g scale). Then the 2-cyanomethylbenzoic acid is obtained with a Beckmann rearrangement of the oxime previously prepared using the para-toluenesulfonylchloride (Yield = 74%). The reaction of the 2-cyanomethylbenzoic acid and 3-amino-5-pyrazole by a microwave-assisted cyclization in acetic acid in sealed vessel provides the isoquinolone in 75% yield (2g scale). Finally, the chlorination is performed using POCl3 to deliver the 1-chloro-3-aminopyrazolylisoquinoline in 61% yield.

Of course the synthesis continues with either O or S nucleophilic substitution on the chlorine atom or by Suzuki cross-coupling, furthermore different substituents can be introduced on either the pyrazole ring or the phenyl ring of the isoquinoline.

WO/2007/071348

Synthesis of 7-Prenylindole

2007-07-02T13:05:00.000-07:00

I have seen some days ago this publication from M. Pirrung concerning the synthesis of 7-Prenylindole starting from indoline. This molecule is key ring in many natural products. As depicted below, the synthesis starts with copper catalyzed N-alkylation of indoline with 2-chloro- 2-methylbut-3-yne in THF in 91% yield on 10 mmol scale. After the reduction of the CC triple bound in alkene, the dimethylallylindoline obtained is submitted to a micro-wave assisted aza-claisen rearrangement in 90% yield (this step has been performed in a monomode micro-wave oven in a sealed tube at 150°C). Finally, the indoline has been oxidized into indole with MnO2 in DCM in 88% Yield.

I like this synthesis first, of course because this is indole ring, but also because the author uses one of my favorite reaction, the aza-claisen rearrangement, and my favorite tool for organic synthesis, a micro-wave oven.

Practical Synthesis of 7-Prenylindole
Xin Xiong and Michael C. Pirrung
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/jo070734v

For the application of the 7-Prenylindole from the same author see:

Glyceraldehyde 3-Phosphate Dehydrogenase Is a Cellular Target of the Insulin Mimic Demethylasterriquinone B1
Hyunsoo Kim, Liu Deng, Xin Xiong, William D. Hunter, Melissa C. Long, and Michael C. Pirrung
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/jm070437i

Synthesis of benzothiazole

2007-06-29T02:42:00.000-07:00

Yes, I am still alive, but lot of work, so not time to post something this last weeks...

Of course I have missed a lot of things, but I will start the most recent chemistry.

In looking the e-first of Synthesis, I discover the one-pot synthesis of benzothiazoles starting from o-haloanilide with a tandem thionation with the Lawesson's reagent and an intramolecular cyclization, the authors propose as mechanism an intramolecular nucleophilic substitution, for me that sounds weird because the best results are obtained with both fluoro and iodio thioanilide, I would propose the formation of radical anion on sulfur or something like this which could be consistent with the results, nonetheless, this is a very interesting transformation.

One-Pot Preparation of 2-(Alkyl)arylbenzothiazoles from the Corresponding o-Halobenzanilides, Dan Bernardi, Lalla Aïcha Ba, Gilbert Kirsch, Synthesis, 2007, e-first.

That reaction reminds me a 2006 JOC have read some months ago, talking about, of course, the synthesis of benzothiazoles starting from simple thioanilides and using Dess-Martin periodinane to promote the cyclization in only 15minutes in DCM. And in their case they propose a radical intramolecular cyclization!!!

Hypervalent Iodine Mediated Intramolecular Cyclization of Thioformanilides: Expeditious Approach to 2-Substituted Benzothiazoles, D. Subhas Bose, Mohd. Idrees,J. Org. Chem. 2006, 71, 8261-8263.

Synthesis of Isradipine

2007-06-12T12:08:00.000-07:00

Isradipine is a drug used to lower blood pressure but recently it was found by a team from Nortwestern University, that this molecule can also slow the progression of Parkinson's disease, and restore the dopamine neurons (In animals tests). Isradipine is a calcium channel blocker of the 1,4-dihydropyridine class with a benzoxadiazole moiety in position 4.
The synthesis of the 1,4-dihydropyridine ring is quite classic, the first step consists in a Knoevenagel reaction of methyl acetoacetate on the benzoxadiazole 4-carboxaldehyde using piperidine and acetic acid as catalyst and diisopropylether as solvent in a 61% yield (this is the first time I see a Knoevenagel reaction in an ether!!!???? DCM, Toluene OK, but maybe I am wrong). The second step of this synthesis is the condensation of the acrylate obtained with the isopropyl aminocrotonate in ethanol to give the desire 1,4-dihydropyridine Isradipine in 67% yield after recrystallisation.

(WO/2005/005437) An improved Process for the Manufacture of Isradipine (Shasun Chemical & Drugs Limited)

Synthesis of Alprazolam

2007-06-11T12:33:00.000-07:00

In reading about Synthesis of Essential Drugs, I have found in my lab (not a very good book, from a chemical point of view, a lot of mistakes), I have come upon a very strange way to synthesize benzodiazepines (actually triazolobenzodiazepines).
This synthesis starts by a nucleophilic substitution of hydrazine on a 2-chloroquinoline (2,6-dichloro-4-phenylquinoline), boiling this hydrazinoquinoline with orthoacetate in xylene affords triazoloquinoline intermediates.

This intermediate undergoes the key step of the synthesis, a oxidative ring opening of the quinoline with sodium periodate and ruthenium oxide, leading to the triazolobenzophenone.

The 1,3,4-triazole is treated with formaldehyde to provide hydroxymethyl intermediate, subsequent bromination using phosphorous tribromide gives bromomethyltriazole which after spontaneous cyclization with ammonia produces the Alprazolam.

Sorry for the lack of informations, I don't have the two patents concerning this molecule.

Solid-Phase Heterocyclic Synthesis

2007-06-11T12:07:00.000-07:00

For those who are interested by heterocyclic synthesis on solid-phase and/or by cycloaddition, will be concerned by a recent review published in Journal of Combinatorial Chemistry by Alvarez and coll., you will find [2+2], [3+2] and [4+2] cycloadditions, and a very small chapter on tandem [4+2]/[3+2].

Advances in Solid-Phase Cycloadditions for Heterocyclic Synthesis
Lidia Feliu, Patricia Vera-Luque, Fernando Albericio, and Mercedes Alvarez
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/cc070019z

Depolymerization of nylon

2007-06-06T12:46:00.000-07:00

The world's annual consumption of plastic materials has increased from around 5 million tonnes in the 1950s to nearly 100 million tonnes today.

For ecological but also for economical reasons, it becomes more and more important to recycle plastics. One way to accomplish this recycling is to develop depolymerization methodologies.

In this area, Kamimura and coll. has published in Organic Letters a very intriguing methodology to depolymerize nylon. They heated 6-nylon at 300°C in a ionic liquid (PP13 TFSI) in presence of DMAP as catalyst for 1h under nitrogen atmosphere until the mixture became homogeneous. After distillation with a Kugelrohr apparatus, the caprolactam was obtained in a 86% yield.

An Efficient Method To Depolymerize Polyamide Plastics: A New Use of Ionic Liquids
Akio Kamimura and Shigehiro Yamamoto
Org. Lett.; 2007; ASAP

Synthesis of Indazole nucleus

2007-06-04T13:17:00.000-07:00

In reading about kinasepro blog, you can notice the important number of biologically active compounds possessing the indazole core (in blue), Axitinib was synthesized by Pfizer and WO/2007/056170 was developed by Baeyer US as potent IGF-1R kinase inhibitors and ABT-102 was developped in Abbot lab and is currently in clinical development for the treatment of chronic pain.

I was looking for a straigthforward synthesis of indazole nucleus, I found a paper from Abbot lab.
They have depicted the synthesis of indazole starting from benzaldehyde with fluorine as leaving group and hydrazine, we can hope in that case to have formation of the hydrazone and subsequent intramolecular cyclization, but the reaction is very low yielding, because the cyclization is very slow and there is a competitive Wolf-Kishner reduction.

With some experiments they have confirmed that the reaction did not proceed via intramolecular cyclization of the hydrazone, but through a transient aminal (obtained by a previous nucleophilic subsitution of hydrazine on fluorine) which give the indazole core after elimination of hydrazine.

In order to circumvent this problem, they condensed the methyloxime on o-fluorobenzaldehydes to avoid Wolf-Kishner elimination, and with hydrazine cleanly gave indazoles. Good Job....

New Practical Synthesis of Indazoles via Condensation of o-Fluorobenzaldehydes and Their O-Methyloximes with Hydrazine
Kirill Lukin, Margaret C. Hsu, Dilinie Fernando, and M. Robert Leanna
J. Org. Chem. 2006, 71, 8166-8172.

Total synthesis of ageladine A

2007-06-03T12:57:00.000-07:00

Sorry for the lack of post last week but I was very busy.
In reading the ASAP of JOC, I found a very interesting paper from Weinreb (ok he has already published on this topic) describing the total synthesis of ageladine A with a 6-pi-1-aza-triene eletrocyclization for the formation of the pyridine ring as key step.

More precisely with the electrocyclization of chloromethoxyimine (synthesized in a single step from a carboxylic acid using carbontetrachloride/PPh3, Methoxyamine hydrochloride with pyridine in acetonitrile with a good yield of 87%) by heating the solution in o-xylene in 150°C to afford the chloropyridine in 84% yield. I find amazing, the first tranformation because starting from a carboxylic acid to chloromethoxyimine, it is possible to achieve different type of reactions, electrocyclization as depicted here, but also cross-coupling reeactions on the chlorine, and certainly synthesize others heterocycles.

Further substitutions, deprotection and a cross-coupling on the chloropyridine have provided the ageladine A as well as analogues for biological evaluation. Interestingly, the synthesis of the imidazole precursor has been synthesized from the tribromoimidazole by sequencial regioselective bromine lithium exchange.

Application of a 6-1-Azatriene Electrocyclization Strategy to the Total Synthesis of the Marine Sponge Metabolite Ageladine A and Biological Evaluation of Synthetic Analogues

Matthew L. Meketa, Steven M. Weinreb, Yoichi Nakao, and Nobuhiro Fusetani

JOC, 2007, ASAP

dichloropyrazine

2007-05-18T13:22:00.000-07:00

I would like to present you today a reaction I have performed a long time ago (in a galaxy far, far away....), and which can be very useful for different purposes.

As you probably know or should know , the regioselective chlorination of pyridine or quinoline N-oxide in the position 2 can be achieved by treatment with phopshorous oxychloride as chlorinating agent.

But, I have realized this reaction on the pyrazine-1,4-dioxide, if you apply the "classic" mechanism on this structure, you should have either the 2,5-dichloro or 2,3-dichloropyrazine, but of course it is not the case and the only compound isolated is the 2,6-dichloropyrazine.

Unfortunately, I have no explanation for this I only know that when the position 6 is blocked then the chlorination occurs in 5 and when position 6 and 5 are blocked the chlorination is in 3.
A don't have the exact references but they were J Het Chem in the mid 80's from a Yamamoto.

Nicotine

2007-05-16T12:49:00.000-07:00

Today, I am a little bit lazy, so I give you one more time some interesting recent literature about hetchem, for the smokers and non-smokers don't forget to read "Recent Advances in the Synthesis of Nicotine and its Derivatives" by Comins, this article is in press in Tetrahedron and should be available soon.

synthesis of quinazolinediones

2007-05-15T08:51:00.000-07:00

Quinazoline is a very important ring in natural product synthesis as well as medicinal chemistry. Today, I want to show you a synthesis described by Timothy T. Curran et al. from Pfizer, Ann Arbor, Michigan, where the quinazolinediones have been synthesized by an intramolecular nucleophilic aromatic substitution, using NaH or NaHMDS to generate the dianion for the cyclization, with yields between 67-83% on multigram scale (R=OMe:520g, R=Me:250g).

By the way, the final molecules are potent gyrase/topoisomerase inhibitors.

Metal-Assisted Multicomponent Reactions Involving

2007-05-13T04:03:00.000-07:00

Today another short-review concerning the multicomponent synthesis of heterocycles with transition metal catalysts involving carbon monoxyde.
This review is mainly about rhodium catalyze hydroformylation.

Angew. Chem. Int. Ed. 2007, 46, 3612 – 3615.

Synthesis of alkylpyridine

2007-05-12T04:41:00.000-07:00

I am just reading the Tetrahedron report number 800 on "Titanium carbenoid reagents for converting carbonyl groups into alkenes" by Hartley and that reminds me a paper of Nicolaou, I read some years ago, concerning the reaction of Titanocene methylidene with isoquinoline N-oxide.

In his paper, KCN noticed that the different "pyridine" N-oxides can be deoxygenated by Tebbe reagent and in the same time the introduction of a methyl group in also possible (in alpha of the N), and regioselectively in the case of isoquinoline. The same reactivity has been observed with Petasis reagent, but with longer time reaction and higher temperature.

Angew. Chem. Int. Ed. 2000, 39, 2529.

Recent progress in catalytic synthesis of imidazoles

2007-05-09T11:42:00.000-07:00

For today, I would like to advise you to read a very interesting review from Shin Kamijo and Yoshinori Yamamoto on the recent progress in catalytic synthesis of imidazoles. This review has been published recently in Chemistry an Asian Journal, and shows different catalytic methodologies, mainly involving transition metal chemistry but also organocatalytic to synthesisze this very useful heterocyclic ring. For people who cannot have this paper, stay on-line I will show you some examples very soon.

Recent Progress in the Catalytic Synthesis of Imidazoles
Shin Kamijo and Yoshinori Yamamoto
Chem. Asian J. 2007, 2, 568 – 578.

Synthesis of 2-Ethyl-1,2,3,4-tetrahydroquinoxaline

2007-05-02T11:56:00.000-07:00

In 2006, Lectka et al. described the synthesis of quinazolinones by a catalytic, enantioselective hetero-Diels-Alder reaction. The key point of this synthesis is the double activation of the diene (diazadiene) in one hand and the dienophile in the other hand.
Activation of o-Benzoquinone diimide (diene) has been achieved by zinc (II) triflate, whereas activation of ketene enolate (dienophile) by benzoylquinidine starting from corresponding acide chloride. This reaction has been performed in THF at -78°C to give a single enantiomer (%ee >99) in 76% yield. Finally the reduction of both benzoyl group and quinoxalinone with LiAlH4 has provided the 2-Ethyl-1,2,3,4-tetrahydroquinoxaline, which is an inhibitor of cholesteryl ester transfer protein.

Ref: J. AM. CHEM. SOC. 2006, 128, 13370-13371

For the synthesis of o-Benzoquinone diimide see:
J. Am. Chem. Soc. 1954, 76, 2763-2769.

Synthesis of the camptothecin core

2007-04-17T09:34:00.000-07:00

The post of today deals with the synthesis of the camptothecin core.

This synthesis described by Fortunak in 1996, has an intramolecular Diels-Alder [4+2] cycloaddition as key step between an unactivated alkyne and a imidate generated in situ by action of Me3OBF4 on a N-arylamide.

Tetrahedron Letters, Vol. 37, No. 32, pp. 5679-5682, 1996

This synthesis has been recently improved by Yao et al. using a mixture of Ph3PO and Tf2O (2:1) instead of Me3OBF4, by this methodology a wide range of tetracyclic "camptothecin-like" molecules has been synthesized.

Organic Letters, ASAP, April 14, 2007

Synthesis of methyl 5-methylpicolinate or methyl 5-methylpyridine-2-carboxylate

2007-04-14T08:12:00.000-07:00

The post of today concerns a very beautiful synthesis of the pyridine ring, and more precisely of methyl pyridine-2-carboxylate. This synthesis has been described by Danheiser et al. and with a "imination" of the Meldrum's acid with sodium nitrite (NaNO2) followed by tosylation (TosCl). The tosylimine obtained has been engaged in aluminium catalyzed (Et2AlCl) Diels-Alder reaction with isoprene as diene (of course other dienes can be used, see reference), the bicyclic spiro compound has been treated by sodium methylate, N-chlorosuccinimide in a THF/MeOH mixture to give the desired methyl 5-methylpyridinecarboxylate.

Ref: Organic Syntheses, Vol. 80, p.133 (2003).

I am Back

2007-03-25T07:22:00.000-07:00

Sorry everybody, I was very busy during this last month, I am currently working in a new lab, with new projects, new supervisors, new labmates new reponsabilities, so everything is new, including chemistry (more aliphatic) but the heterocycles are still here, but quite different....

Synthesis of 2,3-substituted indole

2007-03-25T06:49:00.000-07:00

For this come back, I propose you a titanium mediated synthesis of indole (intramolecular McMurry reaction) described some years ago by A. Fürstner starting from disubstituted aromatic rings, ketones in one hand and carboxamides in the other hand. The reaction is conducted in DME (dimethoxyethane) with TiCl3 and Zinc dust to provide different indole ring with good yield.

Organic Syntheses, Coll. Vol. 10, p.382 (2004); Vol. 76, p.142 (1999).

Synthesis of 2,3-Dihydro-pyrrolopyridinones

2007-02-16T04:12:00.000-08:00

Recently, Bischoff et al. has described the synthesis of 2,3-Dihydropyrrolopyridinone by a tandem aminomethylation-Cyclization using in situ generated formimine and an ortho-lithiated pyridinecarboxamide, depending on the reaction conditions it is also possible to continue the cascade reaction with a bis alkylation of the pyrrolidinone ring.

Org. Lett.; (Letter); 2006; 8(25); 5889-5892.

3-arylquinoline

2007-02-15T05:19:00.000-08:00

Side reactions in organic chemistry can be considered as a failure in a target oriented synthesis, but it can be a valuable source a inspiration for the design of new methodologies.
In 2004, Baldwin and coll. tried to synthesize the 5,5',6,6'-tetrahydroxy-3,3'-biindolyl, a potent antioxidant, he proposed as key step a bis-cyclization of the two 2-aminoaryl substituents on the furan (as 1,4-dialdheyde precursor).

Cyclization was attempted with para-toluenesulfonic acid in benzene, and lead to the formation of a 3-arylquinoline in poor 25% yield along with the starting material.

Finally, the 3,3'-biindole has been synthesized by a palladium catalyzed homocoupling reaction from the corresponding 3-iodoindole.

For the mechanism of the quinoline formation and other informations see:

Tetrahedron 60 (2004) 3695–3712

SYNTHESIS OF 3,4-disubstitutedpyrrole-2,5-dicarboxylate

2007-02-13T04:27:00.000-08:00

The post of today is an elegant synthesis of tetrasubstituted pyrrole from a pyridazine ring, this synthesis has been described by Dale Boger et al. and require only zinc metal (9-20 equiv. and previously activated(1)) and acetic acid (0.09M), this transformation is performed in about 24h at room temperature with moderate to good yields (42-70%).

(1) Fieser, L. F.; Fieser, M. "Reagents for Organic Synthesis"; Wiley: New York, 1967; Vol. 1, p.
1276.

For more information about the procedure and the synthesis of pyridazine see:
Organic Syntheses, Coll. Vol. 9, p.335 (1998); Vol. 70, p.79 (1992).

SYNTHESIS OF 3-HydroxyCinchoninic acid

2007-02-08T09:10:00.000-08:00

The synthesis of the 3-hydroxycinchoninic acid has been performed with the reaction a commercially available isatin in presence of chloropyruvic acid (previously synthesized from pyruvic acid and sulfuryl chloride in 95-98% Yield.) in a aqueous potassium hydroxyde solution. After the workup the 3-hydroxycinchoninic acid is isolated as a yellow solid(60-71%).

For more information:

Organic Syntheses, Coll. Vol. 5, p.635 (1973); Vol. 40, p.54 (1960).

James Cason and James D. Willett.

SYNTHESIS OF 2,3-PYRAZINEDICARBOXYLIC ACID

2007-02-08T02:54:00.000-08:00

I will start this blog with a quite old but very interesting synthesis of pyrazine dicarboxylic acid.

This synthesis starts with the formation of quinoxaline, by the reaction of glyoxal and o-phenylendiamine in water with a 85-90% yield(1). Then the benzene fused ring is cleaved with a hot aqueous potassium permanganate solution (2), the mixture is cooled at room temperature and acidified with a 36% hydrochloric acid (3). The crude material is filtered off and recristallized in acetone to give the 2,3-pyrazinedicarboxylic acid with a 75-77% yield.

Interestingly, this synthesis can be applied to quinolines, isoquinolines and naphtalenes to provide the corresponding dicarboxylic derivatives.

For more information:

2,3-PYRAZINEDICARBOXYLIC ACID

Organic Syntheses, Coll. Vol. 4, p.824 (1963); Vol. 30, p.86 (1950).

Reuben G. Jones and Keith C. McLaughlin.

2007-02-08T02:43:00.000-08:00

Welcome to my Blog Dedicated to Heterocyclic Chemistry.

You will find here different ways to synthesize and to functionalize heterocyclic rings, mainly 6-membered rings but not only.

I will try to keep this blog update ASAP.

ENJOY.